■大约3-4%的非小细胞肺癌(NSCLC)患者具有MET外显子14(METex14)跳跃突变。我们报告了gumarontinib/2期研究的2期主要结果,一个选择性的,强力,口服MET抑制剂,在METex14跳跃突变阳性(METex14阳性)NSCLC患者中。
■单臂,多中心,开放标签,GLORY研究的第二阶段在中国和日本的42个中心进行。患有局部晚期或转移性METex14阳性NSCLC的成年人在连续21天的周期内每天一次口服300mg的gumarontinib,直至疾病进展,不能耐受的毒性,或撤回同意。符合条件的患者先前有一或两行治疗失败(不包括MET抑制剂),不符合/拒绝化疗,并且没有标准疗法可靶向的遗传改变。主要终点是具有有效基线肿瘤评估的患者的客观反应率,通过盲目的独立审查。该研究在ClinicalTrials.gov(NCT04270591)注册。
■在2019年8月2日至2021年4月28日之间,招募了84例患者并接受了古马罗替尼(中位随访13.5个月[IQR8.7-17.1]),在数据截止时(2022年4月28日),5例METex14状态无法由中心实验室确认的患者被排除在疗效分析之外.总体客观缓解率为66%(95%CI54-76)(n=79),71%(95%CI55-83)的未治疗患者(n=44),和60%(95%CI42-76)在以前接受过治疗的患者中(n=35)。最常见的治疗相关不良事件(任何级别)是水肿(67/84患者,80%)和低白蛋白尿(32/84,38%)。45例(54%)患者发生≥3级治疗引起的不良事件。导致永久停药的治疗相关不良事件发生在8%(7/84)的患者中。
■Gumarontinib单药治疗在一线或以后使用时,对局部晚期或转移性METex14阳性NSCLC患者具有持久的抗肿瘤活性,毒性可控。
■海河生物制药有限公司,中国国家科技重大专项“古马龙替尼临床研究”部分资助,高选择性MET抑制剂“(2018ZX09711002-011-003);国家自然科学基金(82030045至S.L.和82172633至YF。Y);上海市科学技术委员会研究项目(19411950500至S.L.);上海申康行动计划(16CR3005A至S.L.)和上海胸科医院协同创新项目(YJXT20190105至S.L.)。
UNASSIGNED: Approximately 3-4% of patients with non-small-cell lung cancer (NSCLC) have MET exon 14 (METex14) skipping mutations. We report primary results from the phase 2 stage of a phase 1b/2 study of gumarontinib, a selective, potent, oral MET inhibitor, in patients with METex14 skipping mutation-positive (METex14-positive) NSCLC.
UNASSIGNED: The single-arm, multicentre, open-label, phase 2 stage of the GLORY study was conducted at 42 centres across China and Japan. Adults with locally advanced or metastatic METex14-positive NSCLC received oral gumarontinib 300 mg once daily in continuous 21-day cycles until disease progression, intolerable toxicity, or withdrawal of consent. Eligible patients had failed one or two prior lines of therapy (not including a MET inhibitor), were ineligible for/refused chemotherapy, and had no genetic alterations targetable with standard therapies. The primary endpoint was objective response rate in patients with a valid baseline tumour assessment, by blinded independent review. The study was registered at ClinicalTrials.gov (NCT04270591).
UNASSIGNED: Between Aug 2, 2019 and Apr 28, 2021, 84 patients were enrolled and received gumarontinib (median follow-up 13.5 months [IQR 8.7-17.1]), at data cut-off (Apr 28, 2022) five patients whose METex14 status could not be confirmed by a central laboratory were excluded from the efficacy analysis. The objective response rate was 66% (95% CI 54-76) overall (n = 79), 71% (95% CI 55-83) in treatment-naïve patients (n = 44), and 60% (95% CI 42-76) in previously-treated patients (n = 35). The most common treatment-related adverse events (any grade) were oedema (67/84 patients, 80%) and hypoalbuminuria (32/84, 38%). Grade ≥3 treatment-emergent adverse events occurred in 45 (54%) patients. Treatment-related adverse events leading to permanent discontinuation occurred in 8% (7/84) of patients.
UNASSIGNED: Gumarontinib monotherapy had durable antitumour activity with manageable toxicity in patients with locally advanced or metastatic METex14-positive NSCLC when used in first line or later.
UNASSIGNED: Haihe Biopharma Co., Ltd. Supported in part by grants from the National Science and Technology Major Project of China for \"Clinical Research of Gumarontinib, a highly selective MET inhibitor\" (2018ZX09711002-011-003); the National Natural Science Foundation of China (82030045 to S.L. and 82172633 to YF.Y); Shanghai Municipal Science & Technology Commission Research Project (19411950500 to S.L.); Shanghai Shenkang Action Plan (16CR3005A to S.L.) and Shanghai Chest Hospital Project of Collaborative Innovation (YJXT20190105 to S.L.).